Profiles associated with significant hepatic fibrosis consisting of alanine aminotransferase >30 U/L, exercise habits, and metabolic dysfunction‐associated steatotic liver disease

Posted on by
Profiles associated with significant hepatic fibrosis consisting of alanine aminotransferase >30 U/L, exercise habits, and metabolic dysfunction-associated steatotic liver disease

This study aimed to investigate independent factors and profiles associated with significant hepatic fibrosis, including alanine aminotransferase (ALT) levels >30 U/L in health check-up examinees. Of the patients aged ≥65 years, 35% had significant hepatic fibrosis, moreover, of the patients aged ≥65 years with ALT levels >30 U/L, 52% had significant hepatic fibrosis. ALT levels >30 U/L may be involved in the pathogenesis of significant hepatic fibrosis in patients ≥65 years.


Abstract

Aim

In patients with steatotic liver disease (SLD), significant hepatic fibrosis is a prognostic factor with various etiologies, including inflammation and metabolic dysfunction. This study aimed to investigate independent factors and profiles associated with significant hepatic fibrosis, including alanine aminotransferase (ALT) levels >30 U/L and metabolic dysfunction-associated SLD (MASLD), in health check-up examinees.

Methods

This single-center, retrospective, observational cohort study enrolled 1378 consecutive health checkup examinees from April 2018 to September 2022. Shear wave elastography (SWE) was performed during a routine ultrasound examination, and patients with liver stiffness ≥6.60 kPa were defined as having significant hepatic fibrosis. Patients were classified into nonsignificant hepatic fibrosis (n = 1220) or a significant hepatic fibrosis (n = 158) group according to this definition.

Results

In multivariate analysis, the independent factor for significant hepatic fibrosis was aging (≥65 years; OR 9.637, 95% CI 6.704–13.852, p < 0.0001). According to decision tree analysis, the initial classifier was aging (≥65 years). After aging, an ALT level >30 U/L was the second relevant factor for significant hepatic fibrosis, regardless of age. An undirected graphical model showed that an ALT level of >30 U/L was directly associated with significant hepatic fibrosis. In patients aged ≥65 years with an ALT level >30 U/L, significant hepatic fibrosis was observed in 52% of the patients. Meanwhile, in patients aged ≥65 years with an ALT level ≤30 U/L, MASLD was the third classifier, with significant hepatic fibrosis observed in 38% of patients.

Conclusions

ALT levels >30 U/L and MASLD may be involved in the pathogenesis of significant hepatic fibrosis in patients aged ≥65 years.

A comparative study of hepatic steatosis using two different qualitative ultrasound techniques measured based on magnetic resonance imaging‐derived proton density fat fraction

Posted on by
A comparative study of hepatic steatosis using two different qualitative ultrasound techniques measured based on magnetic resonance imaging-derived proton density fat fraction

Improved algorithm of attenuation measurement showed the strong correlation with magnetic resonance imaging-derived proton density fat fraction. An area under the receiver operating characteristic curve of 0.926 was used for discriminating grade ≥1 steatosis. Improved algorithm of attenuation measurement is an accurate and simple method for quantifying hepatic steatosis and is expected to be used clinically in the future.


Abstract

Aim

This study aimed to evaluate the diagnostic performance of attenuation measurement (ATT; dual-frequency method) and improved algorithm of ATT (iATT; reference method) for the assessment of hepatic steatosis using magnetic resonance imaging (MRI)-derived proton density fat fraction (PDFF) as the reference standard.

Methods

We prospectively analyzed 427 patients with chronic liver disease who underwent ATT, iATT, or MRI-derived PDFF. Correlation coefficients were analyzed, and diagnostic values were evaluated by area under the receiver operating characteristic curve (AUROC). The steatosis grade was categorized as S0 (<5.2%), S1 (≥5.2%, <11.3%), S2 (≥11.3%, <17.1%), and S3 (≥17.1%) according to MRI-derived PDFF values.

Results

The median ATT and iATT values were 0.61 dB/cm/MHz (interquartile range 0.55–0.67 dB/cm/MHz) and 0.66 dB/cm/MHz (interquartile range 0.57–0.77 dB/cm/MHz). ATT and iATT values increased significantly as the steatosis grade increased in the order S0, S1, S2, and S3 (p < 0.001). The correlation coefficients between ATT or iATT values and MRI-derived PDFF values were 0.533 (95% confidence interval [CI] 0.477–0.610) and 0.803 (95% CI 0.766–0.834), with a significant difference between them (p < 0.001). For the detection of hepatic steatosis of ≥S1, ≥S2, and ≥S3, iATT yielded AUROCs of 0.926 (95% CI 0.901–0.951), 0.913 (95% CI 0.885–0.941), and 0.902 (95% CI 0.869–0.935), with significantly higher AUROC values than for ATT (p < 0.001, p < 0.001, p = 0.001).

Conclusion

iATT showed excellent diagnostic performance for hepatic steatosis, and was strongly correlated with MRI-derived PDFF, with AUROCs of ≥0.900.

Genetic analysis of body weight and growth curve parameters in Muzaffarnagari sheep of India

Posted on by

Abstract

The objective of this study was to estimate genetic effects on parameters of the Brody and Richards growth curves using body weight records from birth to 12 months of age on 2287 Muzaffarnagari lamb for a period of 29 years (1976–2004). Estimated growth curve parameters were analysed using six univariate animal models, and genetic correlations among and between the parameters of each function and between parameters of the functions and observed birth and yearling weights were estimated using bivariate analyses. Significant environmental factors including birth year, sex, season, birth status and dam parity were included as fixed effects in all models. Likelihood ratio tests indicated that maternal genetic effects were significant only for birth weight (BW) and degree of maturity at birth (u 0) for the Brody and Richards functions. For these traits, direct heritabilities were similar (0.21, 0.19 and 0.17, respectively), but the estimated maternal heritability for BW (0.18) was twice that of u 0 for both functions. Heritabilites for yearling weight and asymptotic final body weights for the Brody and Richards functions were 0.28, 0.17 and 0.21, respectively. The remaining growth curve parameters were lowly heritable, ranging from zero for the predicted degree of maturity at the age of maximum growth rate for the Richards function to 0.08 for the maturing rate parameter of the Brody function. Genetic correlations between corresponding parameters for different growth functions exceeded 0.88. Our results showed that the Brody and Richards functions had similar genetic architecture, but the Richards function had no apparent advantages over the more easily interpreted Brody function. Failure to identify maternal genetic effects on maturing rate parameters suggested that both functions failed to identify potentially important maternal genetic effects. Therefore, there is no usefulness of estimated growth curve parameters in selection compared to the simple multi-trait genetic evaluations of individual body weights.

Estimation of additive and maternal covariance of production traits in Murrah buffalo

Posted on by

Abstract

The study was done to determine additive, maternal and common permanent environmental effects and best-suited model for some production traits using six univariate animal models that differed in the (co)variance components fitted to assess the importance of maternal effect using likelihood ratio test in Murrah buffaloes. Data from 614 Murrah buffaloes related to production traits were collected from history pedigree sheets maintained at the buffalo farm, Department of Livestock Production and Management (LPM), LUVAS, Hisar. The production traits under this study were 305 days milk yield (305DMY), peak yield (PY), lactation length (LL), dry period (DP), lactation milk yield (LMY) and wet average (WA). The heritability estimates were in the range of 0.33–0.44 for 305DMY, 0.25–0.51 for PY, 0.05–0.13 for LL, 0.03–0.23 for DP, 0.17–0.40 for LMY and 0.37–0.66 for WA. Model 1 was considered best for most of the traits, viz., 305DMY, PY, LL, LMY and WA followed by model 2 for DP. Covariance and correlated values within the traits caused inflation of heritability in model 3 and model 6. The maximum covariance between the additive and maternal effect was found in trait LMY, which was 14,183.90 in model 3 and the minimum value was also reported in the same trait for model 6, valued at −3522.37. Multivariate analysis showed that all production traits were moderate to high and positively correlated with each other except for DP, which was low and negative genetic and phenotypic correlated. Spearman's rank correlation coefficients of breeding value among all six models were high and significant, ranged from 0.78 to 1.00 for all the traits except DP, therefore any of the models could be taken into account depending upon the availability of data.

Dietary (poly)phenols as modulators of the biophysical properties in endothelial cell membranes: its impact on nitric oxide bioavailability in hypertension

Posted on by
Dietary (poly)phenols as modulators of the biophysical properties in endothelial cell membranes: its impact on nitric oxide bioavailability in hypertension

Age is a risk factor to the onset and progression of hypertension, though adherence to plant-based diets improves blood pressure. Herein, we propose the potential of food (poly)phenols to fluidify cholesterol-rich endothelial membranes and improve the diffusion of nitric oxide (·NO) contributing to enhanced bioavailability of vascular ·NO and the nutritional management of hypertension.


Hypertension is a major contributor to premature death, owing to the associated increased risk of damage to the heart, brain and kidneys. Although hypertension is manageable by medication and lifestyle changes, the risk increases with age. In an increasingly aged society, the incidence of hypertension is escalating, and is expected to increase the prevalence of (cerebro)vascular events and their associated mortality. Adherence to plant-based diets improves blood pressure and vascular markers in individuals with hypertension. Food flavonoids have an inhibitory effect towards angiotensin-converting enzyme (ACE1) and although this effect is greatly diminished upon metabolization, their microbial metabolites have been found to improve endothelial nitric oxide synthase (eNOS) activity. Considering the transmembrane location of ACE1 and eNOS, the ability of (poly)phenols to interact with membrane lipids modulate the cell membrane's biophysical properties and impact on nitric oxide (·NO) synthesis and bioavailability, remain poorly studied. Herein, we provide an overview of the current knowledge on the lipid remodeling of endothelial membranes with age, its impact on the cell membrane's biophysical properties and ·NO permeability across the endothelial barrier. We also discuss the potential of (poly)phenols and other plant-based compounds as key players in hypertension management, and address the caveats and challenges in adopted methodologies.

Lipid droplets and fatty acid‐induced lipotoxicity: in a nutshell

Posted on by
Lipid droplets and fatty acid-induced lipotoxicity: in a nutshell

Fatty acids (FAs) are critical molecules for cell growth, proliferation, and development; but are toxic to cells when present in excess. Eukaryotic cells therefore sequester FAs in organelles called lipid droplets (LDs) until needed. LD synthesis and breakdown are under precise metabolic control, and dysregulation of these pathways is linked to lipotoxicity and diseases.


Lipid droplets (LDs) are fat storage organelles that are conserved from bacteria to humans. LDs are broken down to supply cells with fatty acids (FAs) that can be used as an energy source or membrane synthesis. An overload of FAs disrupts cellular functions and causes lipotoxicity. Thus, by acting as hubs for storing excess fat, LDs prevent lipotoxicity and preserve cellular homeostasis. LD synthesis and turnover have to be precisely regulated to maintain a balanced lipid distribution and allow for cellular adaptation during stress. Here, we discuss how prolonged exposure to excess lipids affects cellular functions, and the roles of LDs in buffering cellular stress focusing on lipotoxicity.

Exploratory prospective, randomized phase II study of neoadjuvant transcatheter arterial chemoembolization plus surgery versus surgery alone for large hepatocellular carcinoma (CSGO‐HBP‐005): Clinical Study Group of Osaka University, Hepato‐Biliary‐Pancreatic Group

Posted on by
Exploratory prospective, randomized phase II study of neoadjuvant transcatheter arterial chemoembolization plus surgery versus surgery alone for large hepatocellular carcinoma (CSGO-HBP-005): Clinical Study Group of Osaka University, Hepato-Biliary-Pancreatic Group

Neoadjuvant transcatheter arterial chemoembolization plus surgery was compared with surgery alone for hepatocellular carcinoma >5 cm in this exploratory, multicenter, randomized phase II study. Neoadjuvant transcatheter arterial chemoembolization allowed delay of surgical treatment without increased morbidity and cancer progress.


Abstract

Aim

Neoadjuvant transcatheter arterial chemoembolization (TACE) for large tumors is controversial, especially in the minimally invasive surgery era. The aim of this study was to compare features between groups treated with neoadjuvant TACE followed by surgery (TACE + surgery) or upfront surgery for hepatocellular carcinoma >5 cm.

Methods

In this exploratory, multicenter, randomized phase I study, the primary measure was 2-year disease-free survival (DFS). Secondary measures were resection rate, necrosis rate by TACE, 2-year overall survival, and site of recurrence. A total of 30 patients were randomly allocated to each arm.

Results

The two arms did not differ in patient characteristics. The median time to surgery from randomization was 48 days for TACE + surgery and 29 for surgery only (p < 0.001). Postoperative morbidities did not differ between arms. The 2-year DFS, overall survival, and resection rates were 56.7%, 80.0%, and 93.3%, respectively, in the TACE + surgery arm, and 56.1%, 89.9%, and 90.0% in the upfront surgery arm. Minimally invasive surgery was carried out in 35.7% in the TACE + surgery arm and in 29.6% in the upfront surgery arm. The median necrosis rate by TACE was 90.0%. In resected specimens, invasion to the hepatic vein was less with TACE + surgery (3.6% vs. 22.2%, p = 0.0380). In cases of 100% necrosis with TACE, 2-year DFS was 100%. Site of recurrence did not differ between groups.

Conclusion

Neoadjuvant TACE did not improve 2-year DFS, and neoadjuvant TACE allowed delay of surgical treatment without increased morbidity and cancer progress.

Clinical trial registration

UMIN: 000005241.

Attenuation of hepatitis A antibody after immunization with hepatitis A vaccine (Aimmugen) in people living with HIV

Posted on by

Abstract

Aim

Hepatitis A (HA) is a vaccine-preventable disease. In regions with good sanitation, men who have sex with men (MSM) are the key affected populations. During the 2018–2019 HA outbreak among MSM in Japan, we actively vaccinated MSM living with HIV (MSM-LWHIV) with Aimmugen. As previously reported, their antibody seroconversion rate due to vaccination was lower than that of healthy individuals. However, the durability of Aimmugen in people living with HIV has not yet been reported. We evaluated attenuation after the one-series vaccination (comprising three inoculations) and the factors associated with attenuation.

Methods

We retrospectively examined anti-HA immunoglobulin G (anti-HA-IgG) titers and other clinical data from our hospital's medical records. Patients with no history of vaccination or HA infection (i.e., negative HA-IgG titers) who received one series of Aimmugen, achieved seropositivity, and anti-HA-IgG antibodies were tested ≥2 years after three doses were included. Fisher’s exact test and the Mann–Whitney U-test were performed. p < 0.05 was considered statistically significant.

Results

Fifty-one MSM-LWHIV were included. All were seropositive after the third dose with a median HA-IgG titer of 10.1 (interquartile range, 7.2–12.2) (sample/cut-off values [s/co]). In 45 (40–49) months, seropositivity decreased to 90% (46/51) and was attenuated to a median of 4.4 (2.3–6.5) s/co. Lower baseline B cell counts (p = 0.049), lower anti-HA-IgG levels after the second dose (p = 0.002), and lower anti-HA-IgG levels after the third dose (p = 0.003) were associated with seronegativity.

Conclusions

Anti-HA-IgG titers of vaccinated MSM-LWHIV may be attenuated; thus, additional immunizations should be considered.

Functional interplay of lipid droplets and mitochondria

Posted on by
Functional interplay of lipid droplets and mitochondria

Lipid droplets (LDs) make physical contacts with various organelles in eukaryotic cells including mitochondria. The existence of these contacts is well-known but poorly described. Here, we review recent advances in the understanding of the physical and functional links between LDs and mitochondria, and their implications in fatty acid transfer, cell signaling, and various diseases.


Our body stores energy mostly in form of fatty acids (FAs) in lipid droplets (LDs). From there the FAs can be mobilized and transferred to peroxisomes and mitochondria. This transfer is dependent on close opposition of LDs and mitochondria and peroxisomes and happens at membrane contact sites. However, the composition and the dynamics of these contact sites is not well understood, which is in part due to the dependence on the metabolic state of the cell and on the cell- and tissue-type. Here, we summarize the current knowledge on the contacts between lipid droplets and mitochondria both in mammals and in the yeast Saccharomyces cerevisiae, in which various contact sites are well studied. We discuss possible functions of the contact site and their implication in disease.

Uncovering mechanisms of interorganelle lipid transport by enzymatic mass tagging

Posted on by
Uncovering mechanisms of interorganelle lipid transport by enzymatic mass tagging

Lipid transport is an essential process that underlies the biogenesis and expansion of organelles. Despite its basic importance, there is a dearth of assays to probe lipid exchange between organelles in vivo. Here we discuss the development of a versatile method called METALIC (Mass tagging-Enabled Tracking of Lipids in Cells), that uses enzyme-based mass tagging of lipids in conjunction with mass spectrometry to track interorganelle lipid transport inside living cells.


Lipid trafficking is critical for the biogenesis and expansion of organelle membranes. Lipid transport proteins (LTPs) have been proposed to facilitate lipid transport at contact sites between organelles. Despite the fundamental importance of LTPs in cell physiology, our knowledge on the mechanisms of interorganelle lipid distribution remains poor due to the scarcity of assays to monitor lipid flux in vivo. In this review, we highlight the recent development of a versatile method named METALIC (Mass tagging-Enabled Tracking of Lipids in Cells), which uses a combination of enzymatic mass tagging and mass spectrometry to track lipid flux between organelles inside living cells. We discuss the methodology, its distinct advantages, limitations as well as its potential to unearth the pipelines of lipid transport and LTP function in vivo.